IGF2BP1-HAX-1 positive feedback loop-mediated HAX-1 overexpression blocks autophagic flux and promotes chemoresistance in nasopharyngeal carcinoma.

Abstract

Autophagy is associated with chemoresistance, which is the leading cause of failure in chemotherapeutic treatments. Among the various aspects of autophagy, autophagic flux serves as a critical indicator for evaluating the dynamic processes involved.We report herein that the multifunctional protein HAX-1 promotes chemoresistance by effectively blocking the fusion of autophagosomes with lysosomes. Complementary mass spectrometric and functional studies also demonstrated that HAX-1 recruits NEDD4 to promote Rab7a degradation and inhibits binding of Rab7a with SNAREs by competitively binding to it. Furthermore, HAX-1 binds IGF2BP1 mRNA, thereby contributing to its stability and translation. Moreover, IGF2BP1 enhanced HAX-1 m6A methylation, thereby enhancing its stability. By way of in-vivo and in-vitro experiments, we confirmed the positive role of the IGF2BP1-HAX-1 feedback loop in chemoresistance. Taken together, our findings provide evidence that monitoring of HAX-1, IGF2BP1, and SQSTM1 levels can serve as useful predictors of clinical outcome and chemoresistance risk. In addition, our data provide new insights into the clinical applications of therapies related to autophagic flux and its associated molecular network in targeting cisplatin chemoresistance in nasopharyngeal carcinoma.